PROJECT SUMMARY This R21 proposal is designed to use cell and mouse models to understand the role of NOTCH-PAX9 signaling pathway in alcohol-induced esophageal injury. We hypothesize that ethanol suppresses esophageal squamous cell differentiation through inhibition of the NOTCH-PAX9 signaling. We plan to test our hypothesis with two specific aims: (1) To determine whether ethanol suppresses esophageal squamous epithelial cell differentiation through inhibition of the NOTCH-PAX9 signaling. (2) To investigate whether NOTCH activation counteracts alcohol-induced esophageal injury. These studies are aimed to elucidate the role of NOTCH-PAX9 signaling in alcohol-induced esophageal injury. If proved true, it will lay down a solid mechanistic foundation to further study NOTCH activation as a novel mechanism-based preventive measure against alcohol-induced esophageal injury.